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HFE polymorphisms affect cellular glutamate regulation

Ryan M Mitchell1, Sang Y Lee, Zachary Simmons

  • 1George M. Leader Family Laboratory, Department of Neurosurgery, Pennsylvania State University College of Medicine/Milton S. Hershey Medical Center, 500 University Drive (H110), Hershey, PA 17033, USA.

Neurobiology of Aging
|June 30, 2009
PubMed

Insights

The HFE H63D gene variant increases glutamate toxicity by altering calcium levels and glutamate transport. This finding links common HFE variants to neurodegenerative disease mechanisms.

Area of Science:

  • Neurogenetics
  • Cellular Biology
  • Neurodegenerative Diseases

Background:

  • HFE gene variants are common in Caucasians.
  • The H63D HFE variant is linked to neurodegenerative diseases.
  • Mechanisms underlying this association require elucidation.

Purpose of the Study:

  • To investigate if HFE H63D variant cells exhibit a phenotype promoting glutamate toxicity.
  • To explore the cellular mechanisms, including calcium and iron regulation, involved.

Main Methods:

  • Developed neuroblastoma cell lines with different HFE polymorphisms.
  • Assessed calcium-induced glutamate secretion and cellular glutamate uptake.
  • Utilized astrocytoma cell lines for endogenous HFE expression confirmation.

Main Results:

  • H63D HFE expression increased calcium-induced glutamate secretion.
  • Cellular glutamate uptake was decreased in H63D variant cells.
  • Altering cellular iron mimicked polymorphism-associated glutamate secretion changes.
  • Intracellular calcium levels were altered in a genotype-specific manner.
  • Minocycline and Trolox effects on glutamate uptake varied by HFE genotype, implicating oxidative stress.

Conclusions:

  • HFE H63D variant cells promote glutamate toxicity through altered calcium homeostasis and glutamate transport.
  • HFE-dependent cellular effects extend beyond iron regulation.
  • The H63D HFE variant may contribute to neurodegeneration via excitotoxicity.

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